Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome

Abstract

CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations.

Figure 1

Organization of Human PIGL and Associated Mutations Schematic representation showing both genomic and protein organization of human PIGL with corresponding mutations as well as functional protein domains including a 20aa transmembrane domain (TMD) and the core de-N-acetylase domain.

Figure 2

Cell Surface Expression of Total GPI Anchor and CD59 Fluorescence-activated cell sorting analysis for two separate GPI anchor markers, CD59 and FLAER, were used on a primary fibroblast line from individual 3988 and an EBV transformed lymphoblast line from individual 33300 to evaluate GPI anchor levels. In both instances, two normal controls were used. Shown is a representation of the two. Dotted lines indicate isotype controls.